Efficacy of biological agents combined with oral immunotherapy (OIT) for food allergy: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Food allergy affects a large population throughout the world. Recently, oral immunotherapy (OIT) has been reported as an effective treatment for severe food allergy. Although OIT was successful in numerous trials in desensitisation, adverse events including anaphylaxis during OIT frequently occur. Additionally, some patients fail to be desensitised after OIT and the response to treatment is often not sustained. As a further adjunctive therapy to facilitate OIT, the role of biological agents has been identified. For example, efficacy and safety of omalizumab as an adjuvant therapy of OIT has become apparent through some RCTs and observational studies. Interest towards this topic is growing worldwide, and ongoing trials will provide additional data on the biologics in food allergy.We aim to systematically analyse the efficacy and safety of OIT combined with biological agents for food allergy. METHODS AND ANALYSIS: This paper provides a protocol for a systematic review of the relevant published analytical studies using an aggregate approach following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. Two authors will perform a comprehensive search for studies on MEDLINE/PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) databases. Subsequently, two independent authors will perform abstract screening, full-text screening and data extraction. A meta-analysis will be conducted as appropriate. ETHICS AND DISSEMINATION: The protocol of this systematic review will be provided in a peer-reviewed journal. As the researchers will not identify the individual patients included in the studies, they do not need to acquire ethics approval. PROSPERO REGISTRATION NUMBER: CRD42022373015.

Clinical Features of Quail Egg Ingestion in Patients with Acquired Tolerance to Hen Eggs: A Case Series Study.

INTRODUCTION: Patients with hen's egg allergy are often instructed to avoid consuming other avian eggs, such as quail eggs. However, it is unclear whether patients with an acquired tolerance to hen eggs continue to avoid consuming quail eggs. This study aimed to evaluate the clinical features of quail egg ingestion. METHODS: This prospective case series included children aged ≥1 year with hen's egg allergy who were recruited between October 2019 and February 2021 in our hospital. We conducted an oral food challenge (OFC) with three boiled quail eggs to evaluate the clinical features of quail egg ingestion in patients with acquired tolerance to hen eggs. The primary outcome was a positive OFC after ingesting three quail eggs. Secondary outcomes were cross-antigenicity between hen and quail eggs observed through the skin prick test (SPT) and pattern of quail egg allergy, comprising the onset of reaction, and severity. The correlation between the diameters of the wheals with SPT in hen and quail eggs was evaluated using the Pearson product-moment correlation coefficient. RESULTS: A total of 62 patients underwent the quail egg OFC. The median (interquartile range) age of the participants was 3 (2-5) years. Thirty-three (53%) patients had a history of anaphylaxis due to hen eggs. The median total immunoglobulin E (IgE) level in patients who underwent the OFC with half a heated whole hen's egg was 271 (98-593) IU/mL. The median specific IgE level in egg white and ovomucoid was 9.7 (3.2-21.5) and 4.4 (1.3-6.9) UA/mL, respectively. The quail egg OFC results revealed that none of the 59 patients who ate the three quail eggs completely had an allergic reaction. The SPT-positive and SPT-negative rates in raw and boiled hen and quail egg whites were both correlated. The diameters of wheals with SPT in raw hen and quail egg whites and yolks were positively correlated. CONCLUSION: Patients with an acquired tolerance to hen eggs may not be required to avoid consuming quail eggs.

[BULLYING IN JAPANESE CHILDREN AND ADOLESCENTS WITH FOOD ALLERGIES].

OBJECTIVE: To elucidate the prevailing circumstances of victimization, including bullying, faced by children afflicted with food allergies in Japan. METHODS: From July to August 2021, we executed a web-based questionnaire survey targeting children with food allergies enrolled in the fourth grade or higher, who sought medical attention at the Department of Pediatrics in Showa University Hospital or were affiliated with three allergy-focused patient associations. The survey aimed to ascertain whether these children had encountered instances of bullying, the nature of the bullying incidents, and whether such acts of bullying triggered allergic symptoms. RESULTS: A total of sixty-six children with food allergies participated in the survey. Among them, forty-five (68%) were male, thirty-three (50%) were attending elementary school, and thirty-five (53%) reported experiencing some form of victimization throughout their lives. Specifically, fourteen (21%) had been subjected to bullying due to their food allergy, with two children being coerced into consuming allergens and one child experiencing symptoms induced by allergen-based bullying. CONCLUSION: It is evident that a significant number of children with food allergies face bullying. Therefore, it is imperative for healthcare providers and parents to acknowledge the inherent risk of bullying as an integral aspect of caring for children with food allergies. Prompt measures should be taken, such as educating both teachers and non-allergic children about this risk.

[INVESTIGATION OF THE IMPACT OF ALLERGIC DISEASE ON CHILDREN'S SARS-CoV-2 VACCINATION DECISIONS].

Background, Objectives: The factors associated with parents' decisions to vaccinate their children with SARS-CoV-2 vaccine and the impact of the coexistence of allergic diseases in their children are unclear. METHODS: A cross-sectional survey was conducted among parents of patients aged 15 years or younger who visited our pediatric allergy outpatient clinic and three partner pediatric clinics between April and May 2021. Survey items included presence or absence of other allergic diseases, and SARS-CoV-2 vaccination preferences and reasons. RESULTS: 646 responses were received, with 568 valid responses (88%). Thirty-eight respondents (6.7%) did not want their children to receive SARS-CoV-2 vaccine. Factors that led parents to reject the SARS-CoV-2 vaccine for their children were the coexistence of food allergies and a low evaluation of the expectations of the safety and preventive effect of the SARS-CoV-2 vaccine. The top reasons for not wanting to vaccinate were related to concerns about side effects to the vaccine. CONCLUSION: In order for parents to make correct decisions regarding SARS-CoV-2 vaccination of their children, it is necessary to create an environment in which up-to-date and correct information is available to avoid excessive anxiety. More care is needed, especially if the child has food allergies.

Relationship between the diagnosis of food protein-induced enterocolitis syndrome and postemetic procalcitonin levels.

Background: There are no reports on the relationship between food protein-induced enterocolitis syndrome (FPIES) diagnosis and procalcitonin levels. Objective: Our study sought to demonstrate a correlation between the presence or absence and severity of FPIES symptoms and postemetic procalcitonin levels. Methods: The subjects were 53 patients with FPIES (44 with hen's egg allergy, 4 with milk allergy, 4 with wheat allergy, and 3 with soy allergy), who collectively underwent a total of 75 oral food challenges (OFCs). Procalcitonin levels at 5 hours after antigen ingestion were compared between patients with a positive OFC result and those with a negative OFC result and between patients who experienced mild or moderate events and those who experienced severe events. Results: At 5 hours after ingestion of the causative food, the median procalcitonin levels in patients with a negative OFC result, patients who experienced a mild or moderate event, and patients who experienced a severe event were 0.02, 0.03, and 0.16 ng/mL, respectively. The procalcitonin level was significantly higher in the groups with a positive OFC result than in the groups with a negative OFC result (P < .001), and it was significantly higher in those who experienced severe events than in those who experienced mild or moderate events (P = .012). Conclusion: Measurement of procalcitonin levels has the potential to provide a quantitative and objective assessment of FPIES diagnosis and severity.

Optimal period for achieving sustained unresponsiveness in peanut oral immunotherapy.

Background: Oral immunotherapy (OIT) can help children with persistent food allergies achieve sustained unresponsiveness (SU). However, the optimal therapeutic period for obtaining SU remains unclear. Objective: We aimed to retrospectively investigate the association between the OIT treatment period and achievement of SU. Methods: We enrolled patients who received OIT for peanut allergy between January 1, 2018 and December 31, 2022. OIT comprised the build-up phase, maintenance phase, complete avoidance, and an oral food challenge (OFC) for confirming SU. The peanut dose in the OFC was gradually increased to 3,000 mg (peanut protein: 795 mg), which was subsequently maintained for ≥5 months. SU was defined as a negative response to 795 mg of peanut protein after ≥2 weeks of complete avoidance. We evaluated the therapeutic OIT period for achieving SU using Kaplan-Meier analysis. Results: Forty-eight patients underwent peanut OIT. The starting age at OIT initiation was 8 (interquartile range [IQR], 7-10) years. Forty-one (85%) patients had a history of anaphylaxis. The median specific immunoglobulin E concentration to peanut and Ara h 2 at OIT initiation was 85.3 (IQR, 33.7-100) and 57.6 (IQR, 21.9-100) UA/mL, respectively. The median observational period was 2.1 (IQR, 1.6-3.0) person-years (PY). Thirty-four (71%) patients achieved SU, with the rate of SU achievement gradually increasing with the therapeutic period. The median period until SU achievement was 2.1 (95% confidence interval, 1.6-2.5) PY. The rate of SU achievement slowed down after 2.7 PY. Conclusion: OIT for at least 2.7 PY can increase the rate of SU achievement. The protocol No. 3107.

[CURRENT STATUS OF FOOD ALLERGY MANAGEMENT IN FOOD SERVICE PROVIDERS].

OBJECTIVE: Assess the current state of food allergy management strategies and the perceptions of them among food service providers. METHODS: The study surveyed establishments that participated in a food allergy management workshop or- ganized by the Tokyo Metropolitan Government in February 2018. The survey inquired about the implemen- tation status of food allergy management strategies, the frequency of accidental ingestions and near misses, and the necessary actions for advancing food allergy management. RESULTS: The survey yielded a response rate of 78% (257/331); 81% of the operators reported having implemented some form of food allergy management strategies. However, only 51% had created a manual for food allergy management and 55% had labeled 7 specified ingredients. 29% of the operators reported experiencing accidental ingestions or near misses, with 34% of those incidents requiring medical attention. 49% of the operators identified the "establishment of industry standards" as a crucial step in advancing food allergy management. CONCLUSION: The survey results indicate that establishments have not fully implemented adequate and effective food allergy management strategies. There is a need to enhance the awareness and understanding of food allergies among businesses and to establish appropriate and sufficient food allergy management measures in the future.

Accidental Ingestion of Allergic Food at Eating-Out and Home Meal Replacement by Children with Food Allergy.

INTRODUCTION: In Japan, there are no regulations for allergy labeling in eating-out and home meal replacement (HMR). Consequently, patients with food allergy are at risk of accidental ingestion when using these services. It is necessary to understand the current situation of accidental food ingestion at eating-out and HMR to consider related legislation in the future. METHODS: A Web-based survey was conducted from August to September 2021 among patients participating in the survey. The survey included information on the use of eating-out and HMR, frequency of accidental ingestion, medical institution visits and treatment, and reasons for accidental ingestion. RESULTS: There were 1,141 valid responses, with 8 (5-15) years as the median age of the participants. Moreover, 769 (67.4%) participants had a history of anaphylaxis, 622 (54.5%) experienced accidental ingestion, of which 485 (42.5%) and 348 (30.6%) occurred while eating-out and at HMR, respectively. A total of 71 (14.6%) and 31 (8.9%) participants who had accidental ingestion while eating-out and at HMR, respectively, required hospitalization. Age, milk allergy, and a history of anaphylaxis were risk factors significantly associated with accidental ingestion. The reasons for the accidental ingestions were personal and store-side error for a total of 438 cases and of 356 cases, respectively. DISCUSSION/CONCLUSION: It is necessary for both stores and patients to take measures to prevent accidental ingestion in eating-out and HMR. Additionally, the fact is that the lack of allergy labeling guidelines for eating-out and HMR is a major factor in the occurrence of accidental ingestion.

Risk Factors for Lung Function Decline in Pediatric Asthma under Treatment: A Retrospective, Multicenter, Observational Study.

Background: Childhood asthma is a major risk for low lung function in later adulthood, but what factors in asthma are associated with the poor lung function during childhood is not known. Objective: To identify clinical factors in children with asthma associated with low or declining lung function during the treatment. Methods: We enrolled children with asthma who had been treated throughout three age periods, i.e., 6−9, 10−12, and 13−15 years old, at seven specialized hospitals in Japan. Clinical information and lung function measurements were retrieved from the electronic chart systems. To characterize the lung function trajectories during each age period, we evaluated the forced expiratory volume 1 (FEV1) with % predicted values and individual changes by the slope (S) from linear regression. We defined four trajectory patterns: normal (Group N) and low (Group L), showing %FEV1 ≥80% or <80% throughout all three periods; upward (Group U) and downward (Group D), showing S ≥ 0 or S < 0%. Logistic regression analysis was performed to compare factors associated with the unfavorable (D/L) versus favorable (N/U) groups. Results: Among 273 eligible patients, 197 (72%) were classified into Group N (n = 150)/U (n = 47), while 76 (28%) were in Group D (n = 66)/L (n = 10). A history of poor asthma control, long-acting beta2 agonist use, and a lower height Z-score during 13−15 years were associated with an unfavorable outcome (Group D/L). Conversely, inhaled corticosteroid (ICS) use during 10−12 years and high-dose ICS use during 13−15 years were associated with a favorable outcome (Group N/U). Conclusion: We identified several factors that are associated with unfavorable lung function changes in pediatric asthma. Attention should be paid to the possible relationship between yearly changes in lung function and poor asthma control, use of ICS (and its dose) and use of LABA.

Evaluation of early laryngeal reaction at oral food challenge.

Background: Open oral food challenge (OFC) is a commonly used diagnostic method for food allergy; however, the occurrence of uncertain reactions leads to inconclusive results. Objective: We aimed to determine the associations between mild laryngeal symptoms and positive results in open OFCs. Methods: We retrospectively investigated medical records of high-risk children (aged 3-15 years) who had undergone open OFC for a low dose of peanuts, hen's egg, cow's milk, or wheat. The OFC result, severity of allergic reactions, and administered treatments during OFCs were compared between the subjects with and without laryngeal symptoms. The risks of a positive OFC result were assessed by using logistic univariate and multivariate analyses, with age, sex, and serum levels of total and food-specific IgE as covariates. Results: Among the 198 patients who underwent OFC, 25 had mild laryngeal symptoms: 8 (32%), 7 (22%), 0 (0%), and 10 (40%) in the OFC trials with hen's egg, cow's milk, wheat, and peanuts, respectively. In the peanut OFCs, univariate analyses revealed a 5-fold higher risk of a positive result (odds ratio = 5.0 [95% CI = 1.1-22.8]) in the symptomatic subjects than in the asymptomatic subjects. However, on multivariate analyses, none of the associations between the symptoms and a positive result were significant in any of the OFCs. The occurrence of anaphylaxis and adrenalin injections did not differ significantly between the symptomatic and asymptomatic subjects. Conclusions: Laryngeal symptoms should be considered a warning sign for a positive OFC result in peanut OFCs, although not critical enough to stop the challenge.

Catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides via selective C-F bond activation.

A regioselective carbosilylation of alkenes has emerged as a powerful strategy to access molecules with functionalized silylated alkanes, by incorporating silyl and carbon groups across an alkene double bond. However, to the best of our knowledge, organic fluorides have never been used in this protocol. Here we disclose the catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides mediated by tBuOK. The main feature of this transformation is the selective activation of the C-F bond of an organic fluoride by the silyl boronate without undergoing potential side-reactions involving C-O, C-Cl, heteroaryl-CH, and even CF3 groups. Various silylated alkanes with tertiary or quaternary carbon centers that have aromatic, hetero-aromatic, and/or aliphatic groups at the ß-position are synthesized in a single step from substituted or non-substituted aryl alkenes. An intramolecular variant of this carbosilylation is also achieved via the reaction of a fluoroarene with a ω-alkenyl side chain and a silyl boronate.

Construction of poly-N-heterocyclic scaffolds via the controlled reactivity of Cu-allenylidene intermediates.

Controlling the sequence of the three consecutive reactive carbon centres of Cu-allenylidene remains a challenge. One of the impressive achievements in this area is the Cu-catalyzed annulation of 4-ethynyl benzoxazinanones, which are transformed into zwitterionic Cu-stabilized allenylidenes that are trapped by interceptors to provide the annulation products. In principle, the reaction proceeds via a preferential γ-attack, while annulation reactions via an α- or ß-attack are infrequent. Herein, we describe a method for controlling the annulation mode, by the manipulation of a CF3 or CH3 substituent, to make it proceed via either a γ-attack or an α- or ß-attack. The annulation of CF3-substituted substrates with sulfamate-imines furnished densely functionalized N-heterocycles with excellent enantioselectivity via a cascade of an internal ß-attack and an external α-attack. CH3-variants were transformed into different heterocycles that possess a spiral skeleton, via a cascade of an internal ß-attack and a hydride α-migration followed by a Diels-Alder reaction.

Effect of oral immunotherapy in children with milk allergy: The ORIMA study.

BACKGROUND: This study was aimed at evaluating the efficacy and safety of oral immunotherapy (OIT) in children with severe cow's milk allergy. METHODS: The subjects comprised 28 children (aged 3-12 years) with allergic symptoms that were induced by ≤ 10 mL of cow's milk in an oral food challenge test (OFC). The subjects were randomly allocated to the treatment group (n = 14) and control group (n = 14); the former received rush immunotherapy for 2 weeks, followed by a gradual increase of cow's milk volume to 100 mL for 1 year, and the latter completely eliminated cow's milk for 1 year. Both groups underwent an OFC with 100 mL of cow's milk after 1 year. RESULTS: The treatment group had significantly higher rates of a negative OFC [7/14 (50%) vs. 0/14 (0%), p < 0.01] compared with the control group. The cow's milk-specific IgE level significantly decreased in the treatment group (p < 0.01) but not in the control group (p = 0.63). During the study period, adrenaline was required in 6/14 patients (43%) of the treatment group and in 0/14 patients (0%) of the control group. Long follow-up data were available at the 2-year point after the study for 8 in the treatment group and 7 (87.5%) of these continued to ingest milk (>100 mL). CONCLUSIONS: The effect of immunotherapy was 50%, but the incidence of adverse events was not low. Further studies focusing on safety is necessary to standardize OIT for cow's milk allergy.

Evaluation of oral immunotherapy efficacy and safety by maintenance dose dependency: A multicenter randomized study.

BACKGROUND: Generally, oral immunotherapy (OIT) aims for daily administration. Recently, the efficacy of treatment with OIT at a low dose has been reported. However, the optimal dose and the evaluation of dose-dependent OIT outcome have not been described. METHODS: A multicenter, parallel, open-labeled, prospective, non-placebo controlled, randomized study enrolled 101 Japanese patients for treatment with OIT. We hypothesized that target dose OIT would induce short-term unresponsiveness (StU) earlier than reduced dose OIT. StU was defined as no response to 6200 mg whole egg, 3400 mg milk, and 2600 mg wheat protein, as evaluated by oral food challenge after 2-week ingestion cessation. To compare the two doses of OIT efficacy, the maximum ingestion doses during the maintenance phase of OIT were divided into 100%-dose or 25%-dose groups against their target StU dose, respectively. A total of 51 patients were assigned to the 100%-dose group [hen's egg (HE) = 26, cow's milk (CM) = 13, wheat = 12] and 50 to the 25%-dose group (HE = 25, CM = 13, wheat = 12). Primary outcome was established by comparing StU at 1 year. Secondary outcome was StU at 2 years and established by comparing allergic symptoms and immunological changes. RESULTS: The year 1 StU rates (%) for the 100%- and 25%-dose groups were 26.9 vs. 20.0 (HE), 7.7 vs. 15.4 (CM), and 50.0 vs. 16.7 (wheat), respectively. The year 2 StU rates were 30.8 vs. 36.0 (HE), 7.7 vs. 23.1 (CM), and 58.3 vs. 58.3 (wheat), respectively. There were no statistically significant differences in StU between years 1 and 2. The total allergic symptom rate in the 25%-dose group was lower than that in the 100%-dose group for egg, milk, and wheat. Antigen-specific IgE levels for egg-white, milk, and wheat decreased at 12 months. CONCLUSIONS: Reduced maintenance dose of egg OIT showed similar therapeutic efficacy to the target dose. However, we were not able to clearly demonstrate the efficacy, particularly for milk and wheat. Reducing the maintenance dose for eggs, milk, and wheat may effectively lower the symptoms associated with their consumption compared to the target OIT dose. Furthermore, aggressive reduction of the maintenance dose might be important for milk and wheat, compared to the 25%-dose OIT. TRIAL REGISTRATION: UMIN000009373, Multicenter Oral Immunotherapy for Hen's Egg, Cow's Milk, and Wheat-Allergic Children at Outpatient Clinic.

[ACTUAL SITUATIONS OF FOOD ALLERGY RELATED EDUCATION AT NUTRITIONIST TRAINING SCHOOL IN JAPAN].

BACKGROUND & AIM: In the clinical field of food allergies, dietary management towards patients is done inadequately. One plausible reason for this is the possible deficiency of food allergy education during the training courses for registered dietitians. This time, we will investigate the actual situations of food allergy education practiced in the training courses of registered dietitians, and reveal the point at issue. METHOD: We conducted a factual survey via mailing method towards registered dietitian and dietitian nutritionist training facilities throughout the whole country. The survey items include the existence of lectures or practical trainings about food allergies, the pre-graduate education of food allergies, and much more. RESULTS: We got answers from 213 facilities (collection rate 75%). Lectures about food allergies were conducted in 96% of the facilities, and the median of the lecture hour was 210 minutes. Similarly, practical trainings were conducted in 74% of the facilities, and the median was 90 minutes. The rate of people who strongly feel the need for food allergy education was 49%, and the rate for people who felt it was 50%. However, the rate of an ideal educational condition was 32%, and the rate of people who didn't have any plans of increasing the number of lectures and practical trainings were 82%. The major reasons for this were, the crammed condition of the curriculums, and the difficulties conducting lectures and practical trainings that span over several fields of expertise. CONCLUSION: In the training courses of registered dietitians, the practice of food allergy education is hardly adequate, and the educational sites seem to recognize the problem, but they are also pessimistic regarding the improvement of the situation due to the difficult problems that were revealed in this survey. From now on, it is strongly expected for the government and its people to work together to improve the current situation.